Leonard Blaschek, May 2023
Disclaimer: I am a plant scientist doing fundamental research. I believe that genetically modified plants can be a powerful tool in adapting agriculture to the changing climate and growing human population, while minimising its impact on the environment. I am also decidedly critical of large companies exploiting these technologies to extract wealth from farmers and consumers. Although I find it near impossible to not let these beliefs shape my writing to some extent, I have tried my best to make this explainer informative and useful to readers regardless of their opinions on the topic.
The genetic code, stored in a molecule called DNA, can be thought of as the blueprint of life. It contains most of the information that the machineries in our bodies need to build and maintain the myriad different building blocks we consist of. Mutations are changes in this blueprint. Many such mutations have no obvious consequences for the organism, often because they occur in parts of the genetic code that are either seemingly superfluous or redundant with other parts. When mutations occur in important parts of the genetic code, however, they can have far-reaching consequences. The fact that many of us can effectively digest milk even as adults is the result of a relatively recent mutation in the genetic code of some of our ancestors. Of course, mutations are not always this convenient. Huntington's disease and sickle cell anaemia for example are also caused by single mutations. Mutations – sometimes with consequences, mostly without – happen all the time. You, your cat and your houseplant have accumulated countless mutations over the years. In a 1 ha field of wheat, for example, our current understanding suggests that one harvest contains roughly 40 billion mutations. In other words, every single piece of Wheat genetic code (taken together, the entire genetic code of an organism is also called its genome) is likely mutated at least once, somewhere in that wheat field.1 The causes for these natural mutations are numerous and include inaccuracies in the cellular machinery replicating and repairing the genetic code as well as damage from stress, UV-light or toxins. Taken together, such mutations are also called natural variation and form the foundation of evolution. In this little explainer, however, I want to focus on another aspect of mutations: How humans use them to their benefit.
Observant farmers have used mutations thousands of years before we understood the molecular mechanism behind them. A plant whose mutations led to characteristics – or traits – that improved the harvest was kept and its seeds sowed for the next growth season. Generations upon generations of this selective propagation resulted in what we now call artificial selection. "Artificial", because it selects traits that are beneficial to us, while natural selection would generally be beneficial to the plant itself. This practice (which of course is much more sophisticated than I make it sound here) is an irreplaceable tool in agriculture and has produced most of our commonly grown crops. A good example for how drastic a species can be changed by traditional breeding is Brassica oleracea. You might be unfamiliar with the Latin name of this species, but you have almost certainly eaten it. Kale, broccoli, cabbage, Brussels sprouts and kohlrabi are all varieties of Brassica oleracea, having been bred from the same wild plant. There are, however, two considerable problems associated with this method of crop improvement. Firstly, it takes a long time. Brussels sprouts and co. have been cultivated at least since the times of the Roman empire and in some cases only reached their current form in recent decades.2 Secondly, it can have unintended side effects. Supermarket tomatoes, for example, grow fast and seem to last forever, but their flavour profile is often ... disappointing.3
The first problem of traditional breeding – the long time-spans involved – can partly be traced back to the tediousness of finding the right mutations. Although mutations are common, chances to find one in exactly the right spot of the genome to improve a given trait are minuscule. A way around the limitations set by natural mutation rates came in the early 20th century. In 1928, L. J. Stadler published his findings that exposure to X-rays or radium induces large numbers of mutations in barley seeds.4 Those so-called mutagenised plants provided a breeding shortcut, because the increased number of mutations meant that beneficial mutations were much easier to find. It didn't take long after this discovery for mutagenised crops to come to market. Thousands of food and ornamental crop varieties derived from mutagenesis – induced by X-rays, gamma-rays or chemicals – are being grown around the world.5 Important examples include widely grown varieties of grapefruit, barley and rice.6 Of course, random mutagenesis did nothing to address the second problem — the unwanted side effects caused by mutations carried along by accident. Instead, it arguably exacerbated this problem because the dramatically increased amount of mutations in mutagenised crops makes unintended and unwanted mutations more likely as well.
The problem of generating beneficial mutations while avoiding unintended side effects called for more precise tools than the figurative sledgehammer of random mutagenesis. An exciting possibility for such precision was opened by the discovery of a wild soil bacterium that is able to insert pieces of genetic material into the genome of plants. With the advent of plant – or green – biotechnology, biologists found ways to insert specific pieces of DNA into the genome of crop varieties by providing them to this bacterium and letting it handle the rest. In cases where the piece of inserted DNA comes from another species, the resulting plants are called transgenic. Given that we generate these plants with the help of a wild bacterium, it is perhaps unsurprising that such transgenic plants occur naturally as well. The perhaps best know example of a crop that has bacterial DNA in its genome – a natural GMO, if you will – is the sweet potato. Human made transgenic crops include cotton and eggplant varieties that are resistant to insect pests, reducing the need for pesticides. Other transgenic crops are resistant to a specific herbicide, allowing farmers to use more of it. As always, the effects of a tool depend on the intent of the wielder.
The most recent seismic change in plant breeding came with the discovery of gene editing. The most popular form of it, CRISPR/Cas9, is based on the ability of bacteria to detect and cut defined sequences of genetic code. Bacteria use this mechanism to find and destroy DNA of attackers. The Nobel prize-winning adaptation of this process by humans on the other hand can be used to change a specific piece of genetic code in an organism. Where traditional breeding and random mutagenesis required farmers to wait for the desired mutation to occur by accident, gene editing allows us to make the desired change directly. 7
Everything I have written to this point was meant to convey a simple message: Mutations are at the heart of all forms of both traditional and modern agriculture. Some are caused by UV-radiation in a field, some by gamma-rays in an atomic garden and some by the bacterial toolbox used in gene editing. It is not always trivial to draw lines between these cases. Are the mutations in a plant accidentally growing on radioactive soil the product of mutagenesis? Is a plant that contains DNA from another species, such as the sweet potato mentioned above, "unnatural", even if that DNA got there without human intervention? Despite, or perhaps because of, such blurry distinctions, these lines need to be drawn. To protect consumers from undisclosed risks or toxins, the food on our supermarket shelves is carefully regulated. As the possibilities of green biotechnology multiplied, so did the intensity of public discourse about its safety. Consequently, the European legislature decided to strictly regulate GM plants and other genetically modified organisms. But what about all the mutagenesis-derived plants already on the market? Considering that they had been used for decades without any obvious problems, and that banning them would significantly disrupt food supply, mutagenised crops were not included in this legislation. That was not universally well received, leading to a challenge in the European Court of Justice. In its ruling, the court clarified that mutagenised crops are GMOs, but that they are explicitly excluded from GMO legislation. The reasoning behind this decision was essentially that mutagenised crops will not be regulated because they have not been regulated in the past.
Of the plants included in the GMO legislation, transgenic plants are a relatively straight-forward case. An application for a new GM variety is handed in to the local authority, which forwards it to the EU. Standing committees deliberate and the member states vote to approve or disapprove. If no majority is reached, the Commission has the final say. As simple as this sounds, only one regulated GM crop – herbicide resistance corn – has ever been approved for cultivation in the EU. Since then, the vote by the member states has never reached a qualified majority. Instead, the member states usually abstain from voting.
It gets weirder with gene edited crops. Part of the requirements of applying for approval of a GM crop is a method to unequivocally distinguish the respective crop from other, non-GM varieties. But here is the twist: A mutation induced by gene editing – or mutagenesis for that matter – is undistinguishable from a "natural" mutation. There is simply no way to tell the difference, because, as far as we know, there is no difference. In practice, this means that it is currently impossible to apply for cultivation approval of a gene edited crop in the EU. Globally, this makes the EU a stark outlier. As of 2022, New Zealand was the only other market in the world that regulated gene edited crops as GMOs.8 The rest of the world treats them the same as mutagenised crops: Approving new varieties based on the consequences of mutations, instead of the mechanism by which they occurred.
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1 This is a calculation by Prof. Detlef Weigel, based on the length of the wheat genetic code and the observed mutation rate in plants [pay-walled]. Don't feel bad about using Sci-Hub to get access to the PDF, the large scientific publishing houses make way too much money.
2 If your back hurts regularly and you're not on TikTok, you likely hated Brussels sprouts as a kid. That's not because your taste buds were unsophisticated, Brussels sprouts were indeed much more bitter up until the 90s. Of course, breeding does not always take millennia; the Green Revolution led to dramatic yield increases within only a decade or two.
3 The reasons for the poor flavour of many modern tomato cultivars are described here. Other interesting examples include the disease susceptibility of bananas or potatoes.
4 The original publication is, again, pay-walled. For access, see footnote 1.
5 The International Atomic Energy Agency keeps a database of registered varieties, but exact numbers are difficult to get because labelling and registration of mutagenised crops are not generally strictly regulated.
6 An overview can be found here [pay-walled], albeit a bit outdated. For access, see footnote 1.
7 Because of this, gene editing is also called directed mutagenesis, including in documents of the European Court of Justice. To avoid confusion between random and directed mutagenesis, I will refer to the latter as gene editing.
8 Considering countries that have enacted regulatory guidelines for gene edited crops.